Epithelial paracellular barrier function, determined primarily by tight junction permeability, is frequently disrupted in disease. In the intestine, barrier loss can be mediated by tumor necrosis ...factor (α) (TNF) signaling and epithelial myosin light chain kinase (MLCK) activation. However, TNF induces only limited alteration of tight junction morphology, and the events that couple structural reorganization to barrier regulation have not been defined. We have used in vivo imaging and transgenic mice expressing fluorescent-tagged occludin and ZO-1 fusion proteins to link occludin endocytosis to TNF-induced tight junction regulation. This endocytosis requires caveolin-1 and is essential for structural and functional tight junction regulation. These data demonstrate that MLCK activation triggers caveolin-1-dependent endocytosis of occludin to effect structural and functional tight junction regulation.
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We present in situ measurements of particle-phase liquid water. Measurements were conducted from 3 June to 15 July 2013 during the Southern Oxidant and Aerosol Study (SOAS) in the southeastern US. ...The region is photochemically active, humid, dominated by biogenic emissions, impacted by anthropogenic pollution, and known to contain high concentrations of organic aerosol mass. Measurements characterized mobility number size distributions of ambient atmospheric aerosols in three states: unperturbed, dry, and dry-humidified. Unperturbed measurements describe the aerosol distribution at ambient temperature and relative humidity. For the dry state, the sample was routed through a cold trap upstream of the inlet then reheated, while for the dry-humidified state the sample was rehumidified after drying. The total volume of water and semi-volatile compounds lost during drying was quantified by differencing dry and unperturbed volumes from the integrated size spectra, while semi-volatile volumes lost during drying were quantified differencing unperturbed and dry-humidified volumes. Results indicate that particle-phase liquid water was always present. Throughout the SOAS campaign, median water mass concentrations at the relative humidity (RH) encountered in the instrument typically ranged from 1 to 5 μg m−3 but were as high as 73 μg m−3. On non-raining days, morning time (06:00–09:00) median mass concentrations exceeded 15 μg m−3. Hygroscopic growth factors followed a diel cycle and exceed 2 from 07:00 to 09:00 local time. The hygroscopicity parameter kappa ranged from 0.14 to 0.46 and hygroscopicity increased with increasing particle size. An observed diel cycle in kappa is consistent with changes in aerosol inorganic content and a dependency of the hygroscopicity parameter on water content. Unperturbed and dry-humidified aerosol volumes did not result in statistically discernible differences, demonstrating that drying did not lead to large losses in dry particle volume. We anticipate that our results will help improve the representation of aerosol water content and aqueous-phase-mediated partitioning of atmospheric water-soluble gases in photochemical models.
Abstract
Summary
B- and T-cell receptor repertoires of the adaptive immune system have become a key target for diagnostics and therapeutics research. Consequently, there is a rapidly growing number ...of bioinformatics tools for immune repertoire analysis. Benchmarking of such tools is crucial for ensuring reproducible and generalizable computational analyses. Currently, however, it remains challenging to create standardized ground truth immune receptor repertoires for immunoinformatics tool benchmarking. Therefore, we developed immuneSIM, an R package that allows the simulation of native-like and aberrant synthetic full-length variable region immune receptor sequences by tuning the following immune receptor features: (i) species and chain type (BCR, TCR, single and paired), (ii) germline gene usage, (iii) occurrence of insertions and deletions, (iv) clonal abundance, (v) somatic hypermutation and (vi) sequence motifs. Each simulated sequence is annotated by the complete set of simulation events that contributed to its in silico generation. immuneSIM permits the benchmarking of key computational tools for immune receptor analysis, such as germline gene annotation, diversity and overlap estimation, sequence similarity, network architecture, clustering analysis and machine learning methods for motif detection.
Availability and implementation
The package is available via https://github.com/GreiffLab/immuneSIM and on CRAN at https://cran.r-project.org/web/packages/immuneSIM. The documentation is hosted at https://immuneSIM.readthedocs.io.
Contact
sai.reddy@ethz.ch or victor.greiff@medisin.uio.no
Supplementary information
Supplementary data are available at Bioinformatics online.
The floating water bridge phenomenon is a freestanding rope-shaped connection of pure liquid water, formed under the influence of a high potential difference (approximately 15 kV). Several recent ...spectroscopic, optical, and neutron scattering studies have suggested that the origin of the bridge is associated with the formation of anisotropic chains of water molecules in the liquid. In this work, high energy X-ray diffraction experiments have been performed on a series of floating water bridges as a function of applied voltage, bridge length, and position within the bridge. The two-dimensional X-ray scattering data showed no direction-dependence, indicating that the bulk water molecules do not exhibit any significant preferred orientation along the electric field. The only structural changes observed were those due to heating, and these effects were found to be the same as for bulk water. These X-ray scattering measurements are supported by molecular dynamics (MD) simulations which were performed under electric fields of 10 ⁶ V/m and 10 ⁹ V/m. Directional structure factor calculations were made from these simulations parallel and perpendicular to the E-field. The 10 ⁶ V/m model showed no significant directional-dependence (anisotropy) in the structure factors. The 10 ⁹ V/m model however, contained molecules aligned by the E-field, and had significant structural anisotropy.
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Humans are one of the few species undergoing an adolescent growth spurt. Because children enter the spurt at different ages making age a poor maturity measure, longitudinal studies are necessary to ...identify the growth patterns and identify commonalities in adolescent growth. The standard maturity determinant, peak height velocity (PHV) timing, is difficult to estimate in individuals due to diurnal, postural, and measurement variation. Using prospective longitudinal populations of healthy children from two North American populations, we compared the timing of the adolescent growth spurt's peak height velocity to normalized heights and hand skeletal maturity radiographs. We found that in healthy children, the adolescent growth spurt is standardized at 90% of final height with similar patterns for children of both sexes beginning at the initiation of the growth spurt. Once children enter the growth spurt, their growth pattern is consistent between children with peak growth at 90% of final height and skeletal maturity closely reflecting growth remaining. This ability to use 90% of final height as easily identified important maturity standard with its close relationship to skeletal maturity represents a significant advance allowing accurate prediction of future growth for individual children and accurate maturity comparisons for future studies of children's growth.
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The formation of secondary organic aerosols (SOAs) combined with the partitioning of semivolatile organic components can impact numerous aerosol properties including cloud condensation nuclei (CCN) ...activity, hygroscopicity, and volatility. During the summer 2013 Southern Oxidant and Aerosol Study (SOAS) field campaign in a rural site in the southeastern United States, a suite of instruments including a CCN counter, a thermodenuder (TD), and a high-resolution time-of-flight aerosol mass spectrometer (AMS) were used to measure CCN activity, aerosol volatility, composition, and oxidation state. Particles were either sampled directly from ambient or through a particle-into-liquid sampler (PILS), allowing the investigation of the water-soluble aerosol component. Ambient aerosols exhibited size-dependent composition with larger particles being more hygroscopic. The hygroscopicity of thermally denuded aerosols was similar between ambient and PILS-generated aerosols and showed limited dependence on volatilization. Results of AMS three-factor positive matrix factorization (PMF) analysis for the PILS-generated aerosols showed that the most hygroscopic components are most likely the most and the least volatile features of the aerosols. No clear relationship was found between organic hygroscopicity and the oxygen-to-carbon ratio; in fact, isoprene-derived organic aerosols (isoprene-OAs) were found to be the most hygroscopic factor, while at the same time being the least oxidized and likely most volatile of all PMF factors. Considering the diurnal variation of each PMF factor and its associated hygroscopicity, isoprene-OA and more-oxidized oxygenated organic aerosols are the prime contributors to hygroscopicity and co-vary with less-oxidized oxygenated organic aerosols in a way that induces the observed diurnal invariance in total organic hygroscopicity. Biomass burning organic aerosols contributed little to aerosol hygroscopicity, which is expected since there was little biomass burning activity during the sampling period examined.
Neutrophil extracellular trap formation (NETosis) and the NLR family pyrin domain containing 3 (NLRP3) inflammasome assembly are associated with a similar spectrum of human disorders. While NETosis ...is known to be regulated by peptidylarginine deiminase 4 (PAD4), the role of the NLRP3 inflammasome in NETosis was not addressed. Here, we establish that under sterile conditions the cannonical NLRP3 inflammasome participates in NETosis. We show apoptosis-associated speck-like protein containing a CARD (ASC) speck assembly and caspase-1 cleavage in stimulated mouse neutrophils without LPS priming. PAD4 was needed for optimal NLRP3 inflammasome assembly by regulating NLRP3 and ASC protein levels post-transcriptionally. Genetic ablation of NLRP3 signaling resulted in impaired NET formation, because NLRP3 supported both nuclear envelope and plasma membrane rupture. Pharmacological inhibition of NLRP3 in either mouse or human neutrophils also diminished NETosis. Finally, NLRP3 deficiency resulted in a lower density of NETs in thrombi produced by a stenosis-induced mouse model of deep vein thrombosis. Altogether, our results indicate a PAD4-dependent formation of the NLRP3 inflammasome in neutrophils and implicate NLRP3 in NETosis under noninfectious conditions
in vitro
and
in vivo
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While grouping/read-across is widely used to fill data gaps, chemical registration dossiers are often rejected due to weak category justifications based on structural similarity only. Metabolomics ...provides a route to robust chemical categories via evidence of shared molecular effects across source and target substances. To gain international acceptance, this approach must demonstrate high reliability, and best-practice guidance is required. The MetAbolomics ring Trial for CHemical groupING (MATCHING), comprising six industrial, government and academic ring-trial partners, evaluated inter-laboratory reproducibility and worked towards best-practice. An independent team selected eight substances (WY-14643, 4-chloro-3-nitroaniline, 17α-methyl-testosterone, trenbolone, aniline, dichlorprop-p, 2-chloroaniline, fenofibrate); ring-trial partners were blinded to their identities and modes-of-action. Plasma samples were derived from 28-day rat tests (two doses per substance), aliquoted, and distributed to partners. Each partner applied their preferred liquid chromatography–mass spectrometry (LC–MS) metabolomics workflows to acquire, process, quality assess, statistically analyze and report their grouping results to the European Chemicals Agency, to ensure the blinding conditions of the ring trial. Five of six partners, whose metabolomics datasets passed quality control, correctly identified the grouping of eight test substances into three categories, for both male and female rats. Strikingly, this was achieved even though a range of metabolomics approaches were used. Through assessing intrastudy quality-control samples, the sixth partner observed high technical variation and was unable to group the substances. By comparing workflows, we conclude that some heterogeneity in metabolomics methods is
not
detrimental to consistent grouping, and that assessing data quality prior to grouping is essential. We recommend development of international guidance for quality-control acceptance criteria. This study demonstrates the reliability of metabolomics for chemical grouping and works towards best-practice.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
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